1. Field of the Invention
The invention relates generally to methods for treating pain associated with chronic pancreatitis in patients. The methods comprise administering a therapeutically effective amount of a pharmaceutical composition comprising human or porcine secretin and a pharmaceutically acceptable carrier.
2. Brief Description of the Related Art
Chronic pancreatitis (CP) is a long-standing inflammation of the pancreas that alters its normal structure and functions. Chronic pancreatitis can present as episodes of acute inflammation in a previously injured pancreas, or as chronic damage with persistent pain or malabsorption. Inflammation of the pancreas that is associated with chronic pancreatitis generally does not heal or improve, gets worse over time, and leads to permanent damage. The inflammation can cause the pancreas to reduce production of enzymes necessary for digestion of fats and other food components. The inflammation is associated with premature activation of trypsin a proteolytic enzyme normally secreted by the pancreas for digestion of food. Pancreatic fluid is produced by the pancreas upon stimulation of the hind brain by human secretin. Stimulation of the pancreas by secretin will wash any activated trypsin from the pancreas ducts and by this action reduce irritation and inflammation by trypsin residues that may have been left in the pancreatic ducts. The presence of mucous or thick pancreatic secretions has been associated with mutations in the CFTR gene and stimulation of pancreatic fluid flow may reduce the mucous in the pancreatic ducts. Human and porcine secretins are associated with Vasoactive Intestinal Peptide (VIP) receptors that are found throughout the brain. In addition, the avidity of human secretin to VIP receptors may be responsible for central pain reduction in conjunction with opioids.
Chronic pain is the primary symptom of chronic pancreatitis. Pain management has been a challenge in this disease, with multiple modalities attempted for use. Pancreatic rest using pancreatic enzyme supplementation, opioid analgesics, nerve blocks, and antioxidants are currently considered the mainstays in treatment that is not amenable to operative intervention. Unfortunately, even with all of these options, pain remains a prominent and persistent problem for this patient population. While opioids have their inherent drawbacks due mainly to the potential for addiction, pancreatic enzyme supplementation, central nerve blocks and antioxidants have demonstrated limited efficacy. If a new modality were available, it would be of great clinical importance in treating patient symptoms.
Many previous animal studies have been presented on the effect of intravenous secretin on acute pancreatitis. These studies have had heterogeneous results in terms of biochemical and histologic outcomes. Though no studies have shown a worse outcome with any group receiving intravenous secretin therapy, the level of improved outcome varied between modest to moderate improvement, especially with toxin induced acute pancreatitis (Lankisch, Digestion (1983) 26:187; Renner, J. Clin. Invest. (1983) 72:1081-92; Keim et al., Hepatogastroenterology (April, 1985) 32(2):91-96).
During the early 1980s, scientists began to note that intraductal pancreatic pressures in chronic pancreatitis may be elevated along with increased pancreatic secretion viscosity (Tympner, Acta Hepatogastroenterol. (1978) 25:73-76; Guy, Gastroenterology 84:102-107 (1983); Madsen, Scand. J. Gastroenterol. (1982)17:553). Based on these observations, investigators tried a variety of methods to either relieve the obstruction or decrease the viscosity within the pancreatic duct system, therefore leading to less back pressure and flares of chronic pancreatitis. Bromhexine is one of the therapeutic attempts to decrease the viscosity of pancreatic fluid. This modality was noted to be helpful in treating pancreatitis due to a mucin producing pancreatic tumors as well as in chronic pancreatitis with chronic protein plugs. Bromhexine was given alone, with radiation, or with intravenous secretin to help remove the stagnant or sludge-like pancreatic juices that were thought to be leading to recurrent pancreatitis and improved pain (Shinohara, Tando (1993) 7:527-534; Noda, Pancreas (1997) 15:209-211). Intravenous secretin was again recently tried to “flush out” the less viscous pancreatic juice, which again was a promising study to try to relieve the back pressure/sludge of chronic pancreatitis (Tsujimoto, Alcohol. Clin. Exp. Res (29)12:272S-276S).
The only human study using subcutaneous secretin as a sole therapeutic modality for chronic pancreatitis was performed in Germany by Tympner and Rosch in 1986 (Hepato-Gastroenterol. 33:159-162 (1986)). In this placebo-controlled study, twice daily injection of 800 CU (160 mcg) depot secretin was given for seven days to 20 patients. This was done under the same premise: patients with CP were noted to have elevated levels of lactoferrin, trypsin, and protein concentrations, and that if one were able to “wash out” the sticky, protein-rich secretion, improved pain may occur. Secretin therapy alone worked: it decreased the viscosity, lactoferrin and trypsin in the drug administration arm. Interestingly, a strong trend towards decreased serum amylase levels was noted. Most importantly, pain levels at the end of the study were significantly improved (p<0.05) in the study arm, even with such small numbers of participants. Unfortunately, there has never been a follow-up study from this group in which intravenous secretin therapy was studied as a sole pain modulating treatment.
Secretin has also been safely demonstrated at a dose of 6 U/kg (1.2 mcg/kg) for intravenous administration (Yamamoto, Digestive Dis. And Sci. 50:2034-2036 (November 2005)). 0.78 mcg/kg was safely given to 12 patients suffering from Zollinger-Ellison Syndrome (ZES), and these findings were confirmed in a validation cohort study (Kuiper, Pancreatology 10(1):14-18 (2010); EPub 19 Mar. 2010).
The largest parental dose of secretin administered in a study was 160 mcg twice a day per patient for 7 days. This dosing regimen was found safe and is at least 333% more than the highest dosing in this study. The 333% dose was administered for 7 consecutive days without consequences.
Various treatments for abdominal pain due to pancreatitis have been disclosed in the prior art.
For example, U.S. Pat. No. 7,459,155 discloses methods for treating abdominal pain due to pancreatitis by administering the proteolytic enzyme seaprose derived from Aspergillus. 
U.S. Patent Application Publication US2005/0070472 discloses methods for treating pancreatitis and pain associated with it by administering amylin, amylin agonists, or amylin analogues.
U.S. Patent Application Publications U.S. 2007/0219222 and U.S. 2009/0143377 disclose methods of treating pain associated with pancreatitis by administration of transient receptor potential A1 (TRPA1) inhibitors.
U.S. Patent Application Publication U.S. 2008/0146611 discloses methods of treating pain associated with pancreatitis by administering transient receptor potential V3 channel inhibitors.
U.S. Patent Application Publication U.S. 2009/0081184 discloses methods of treating abdominal pain associated with various forms of pancreatitis by administering to the patient one or more non-pancreatic protease enzymes.
U.S. Patent Application Publication U.S. 2009/0192558 discloses methods of treating pain resulting from pancreatitis by using a device such as a microstimulator that electrically stimulates the pancreas.
U.S. Patent Application Publication U.S. 2010/0204313 discloses methods of treating abdominal pain associated with various forms of pancreatitis by administering resiniferatoxin to the patient.
What is needed in the art are compositions and methods for treating pain resulting from chronic pancreatitis that is effective yet does not suffer the disadvantages of for example narcotic addition or limited efficacy. The present invention is believed to be an answer to that need.